TY - JOUR
T1 - Common and divergent features of galactose-1-phosphate and fructose-1-phosphate toxicity in yeast
AU - Gibney, Patrick A.
AU - Schieler, Ariel
AU - Chen, Jonathan C.
AU - Bacha-Hummel, Jessie M.
AU - Botstein, Maxim
AU - Volpe, Matthew
AU - Silverman, Sanford J.
AU - Xu, Yifan
AU - Bennett, Bryson D.
AU - Rabinowitz, Joshua D.
AU - Botstein, David
AU - Drubin, David G.
N1 - Funding Information:
We thank members of the Rose, Gammie, and Botstein labs for helpful discussion. We also thank Wei Wang, Donna Storton, Jessica Buckles, Lance Parsons, and Dave Robinson for assistance with Illumina sequencing and analysis. This research was supported by the National Institute of General Medical Sciences Center for Quantitative Biology (GM071508), a National Institutes of Health grant to D.B. (GM046406), a Department of Energy grant to J.R. (DE-SC0012461), and National Institutes of Health grants to P.G. (GM097852) and Calico Life Sciences LLC.
Publisher Copyright:
© 2018 Gibney et al.
PY - 2018/4/15
Y1 - 2018/4/15
N2 - Toxicity resulting from accumulation of sugar-phosphate molecules is an evolutionarily conserved phenomenon, observed in multiple bacterial and eukaryotic systems, including a number of human diseases. However, the molecular mechanisms involved in sugar-phosphate toxicity remain unclear. Using the model eukaryote Saccharomyces cerevisiae, we developed two systems to accumulate human disease-associated sugar-phosphate species. One system utilizes constitutive expression of galactose permease and galactose kinase to accumulate galactose-1-phosphate, while the other system utilizes constitutive expression of a mammalian ketohexokinase gene to accumulate fructose-1-phosphate. These systems advantageously dissociate sugar-phosphate toxicity from metabolic demand for downstream enzymatic products. Using them, we characterized the pathophysiological effects of sugar-phosphate accumulation, in addition to identifying a number of genetic suppressors that repair sugar-phosphate toxicity. By comparing the effects of different sugar-phosphates, and examining the specificity of genetic suppressors, we observed a number of striking similarities and significant differences. These results suggest that sugar-phosphates exert toxic effects, at least in part, through isomer-specific mechanisms rather than through a single general mechanism common to accumulation of any sugar-phosphate.
AB - Toxicity resulting from accumulation of sugar-phosphate molecules is an evolutionarily conserved phenomenon, observed in multiple bacterial and eukaryotic systems, including a number of human diseases. However, the molecular mechanisms involved in sugar-phosphate toxicity remain unclear. Using the model eukaryote Saccharomyces cerevisiae, we developed two systems to accumulate human disease-associated sugar-phosphate species. One system utilizes constitutive expression of galactose permease and galactose kinase to accumulate galactose-1-phosphate, while the other system utilizes constitutive expression of a mammalian ketohexokinase gene to accumulate fructose-1-phosphate. These systems advantageously dissociate sugar-phosphate toxicity from metabolic demand for downstream enzymatic products. Using them, we characterized the pathophysiological effects of sugar-phosphate accumulation, in addition to identifying a number of genetic suppressors that repair sugar-phosphate toxicity. By comparing the effects of different sugar-phosphates, and examining the specificity of genetic suppressors, we observed a number of striking similarities and significant differences. These results suggest that sugar-phosphates exert toxic effects, at least in part, through isomer-specific mechanisms rather than through a single general mechanism common to accumulation of any sugar-phosphate.
UR - http://www.scopus.com/inward/record.url?scp=85046450815&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85046450815&partnerID=8YFLogxK
U2 - 10.1091/mbc.E17-11-0666
DO - 10.1091/mbc.E17-11-0666
M3 - Article
C2 - 29444955
AN - SCOPUS:85046450815
SN - 1059-1524
VL - 29
SP - 897
EP - 910
JO - Molecular biology of the cell
JF - Molecular biology of the cell
IS - 8
ER -